The present invention relates to novel substituted thiazepines useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention bind to the sigma receptor.
A number of benzomorphan opioids which selectively bind to the sigma receptor induce psychotic-like states in humans (Largent, B. L., et al, Journal of Pharmacology and Experimental Therapeutics, 238:739-748 (1986) and Tam, S. W., Proceedings of the National Academy of Sciences, USA 80:6703-6707 (1983)). Additionally, it has been reported that many known antipsychotic agents interact with the sigma receptor (Walker, M. J., et al, Pharmacological Reviews 42:355-402 (1990)). These include haloperidol, rimcazole, remoxapride, and tiospirone (Jain, A. K., et al, International Clinical Psychopharmacology 2:129-133 (1987); Guy, W., et al, Drug Development Research, 3:245-252 (1983); Moore, N. C., et al, American College of Neuropsychopharmacology, Abstract, p. 149 (1985); Lindstrom, L., et al, Psychopharmacology 86:241-243 (1985); Chouinard, G. and Annable, L., Psychopharmacology 84:282-284 (1984); and Chouinard, G. and Turner, L., Psychopharmacology Bulletin 22:267-271 (1986)).
We have surprisingly and unexpectedly found that a series of substituted thiazepines potently and selectively bind to the sigma receptor and are thus useful in the treatment of various psychotic disorders and in particular schizophrenia.